PROJECT SUMMARY/ABSTRACT Transgender men (trans men; assigned female sex at birth but identify as male) are generally thought to be at low risk of HIV acquisition, typically because of the assumption that they have sex with cisgender women (born female, identify as female) which is considered low risk sexual activity. Emerging data from resource-rich settings show that trans men often face many of the same high risks as transgender women (trans women; assigned male sex at birth but identify as female). Trans men report similar rates to trans women of engagement in sex work and engage in unprotected receptive vaginal and/or anal sex with cisgender men. Additionally, they report high sexual risk-taking behaviors including inconsistent condom use which puts them at risk of HIV and other sexually transmitted infections (STIs). Little is known about HIV risk in trans men globally, and no published data are available from sub-Saharan Africa. In partnership with the trans community, we are testing the effectiveness of peer-delivered HIV self-testing, STI self-sampling and pre-exposure prophylaxis (PrEP) for trans women in Uganda in a cluster randomized trial (R34 MH121084). Leveraging the resources of this RCT, this administrative supplement proposes to recruit a new cohort of 50 trans men through respondent driven sampling. We will use mixed methods to gain a deeper understanding of the sexual health experiences and risk behaviors of trans men in Uganda. Guided by the Social Ecological Model, we will conduct in-depth interviews with up to 20 trans men to understand individual, interpersonal, community and social contextual factors that influence sexual risk behaviors and HIV/STI risk (Aim 1). In Aim 2, we will characterize HIV and STI prevalence and risk among trans men by conducting a behavioral HIV risk assessment including sexual practices, alcohol and drug use, partner violence, gender dysphoria, male hormone use and willingness to take PrEP. In Aim 3, we will evaluate PrEP uptake and persistence among HIV-negative trans men with HIV risk. Participants will be offered PrEP and followed monthly for 12 months. At quarterly visits, participants will receive integrated next steps adherence counseling and drug level feedback using a point-of-care urine tenofovir lateral-flow immunoassay. Free testing and treatment of common curable STIs (Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis) will be provided. Primary outcomes are: 1) PrEP uptake, and 2) persistence at 6 and 12 months as measured by tenofovir levels in dried blood spots collected quarterly. Assessment of PrEP use by trans men will help increase the utilization of HIV services, including HIV and STI testing and PrEP, with a goal of decreasing HIV acquisition. Simultaneous evaluation of prevention uptake among trans women (in the parent R34 trial) and trans men (in this administrative supplement) is an efficient and timely approach to optimizing prevention delivery for trans people. Pilot data from trans men will provide uniquely valuable information to inform future scale-up of combination HIV prevention interventions. This will be the first study, to our knowledge, to assess HIV and STI risk among trans men in sub-Saharan Africa. This project is supported by the Uganda Ministry of Health.